Process for the preparation of l-alpha-hydrazino-beta-phenylpropionic acids

ABSTRACT

PROCESS FOR PREPARING L-A-HYDRAZINO-B-PHENYLPROPIONIC ACIDS BY AMINATING L-A-ACYLAMINO-B-PHENYLPROPIONITRILE WITH CHLORAMINE OR METHOXYAMINE FOLLOWED BY ACID HYDROLYSIS TO FORM THE L-A-HYDRAZINO-B-PHENYLPROPIONIC ACID COMPOUNDS.

United States Patent Oflice 3,794,681 Patented Feb. 26, 1974 3,794,681 PROCESS FOR THE PREPARATION OF L-u-HY- DRAZINO-,/3-PHENYLPROPIONIC ACIDS Meyer Sletzinger, North Plainfield, Sandor Karady, Elizabeth, Manuel G. Ly, New Brunswick, and Seemon H. Pines, Murray Hill, N.J., assignors to Merck & Co., Inc., Rahway, NJ.

No Drawing. Original application Feb. 24, 1970, Ser. No. 13,770, now Patent No. 3,676,480. Divided and this application June 24, 1971, Ser. No. 156,556

Int. Cl. C07c 101/72 U.S. Cl. 260-519 1 Claim ABSTRACT OF THE DISCLOSURE Process for preparing L-a-hydrazino[3-phenylpropionic acids by aminating L-a-acylamino- 3-phenylpropionitrile with chloramine or methoxyamine followed by acid hydrolysis to form the L-u-hydrazino-fl-phenylpropionic acid compounds.

This application is a division of US. Ser. No. 13,770, filed Feb. 24, 1970, now Pat. No. 3,676,480.

This invention relates to novel and useful chemical compounds and to a process for their preparation. More particularly, it relates to novel compounds which are intermediates in the preparation of L-a-hydrazino-B- phenyl-alkanoic acids.

It is known in the art that various a-hydrazino-B- phenyl-alkanoic acids are useful as decarboxylase inhibitors. It is further known that the D-isomer of these acids is generally inactive and may even be antagonistic to the action of the L-form, thereby reducing its potency.

In the past, it has been the accepted practice to separate stereoisomers by the formation of diastereomeric salts with either optically active bases or acids, depending on the nature of the racemate. However, with the hydrazino compounds of the present invention, separation is complicated by the fact that some diastereomeric salts do not form crystalline materials with sufiiciently dilferent properties so that the diastereomers can be readily crystallized. In some instances, the diastereomeric salts are oily or waxy materials which become difiicult if not impossible to separate by conventional means. Quite obviously, if a relatively simple and inexpensive process could be found which would preferentially produce the desired L-a-hydrazino-B-phenyl-alkanoic acids, it would receive widespread acceptance in the art.

Accordingly, it is an object of this invention to prepare novel intermediate compounds. A further object of this invention is to provide a process for the formation of such intermediates. A still further object is to provide a process by which the novel intermediate products of this invention may be formed into useful final products. Other objects will become apparent from the ensuing description of this invention. 7

These objects are accomplished by the present invention which provides the L form of a compound of the formula:

wherein:

wherein R is loweralkyl, or COOH; and R is loweralkanoyl or aroyl.

The loweralkoxy radical signifies an alkoxy group containing from 1 to about 6 carbon atoms and the loweralkyl radical signifies an alkyl group containing from 1 to about 6 carbon atoms which can be straight chained or branched. While in the most preferred compounds of this invention R is loweralkanoyl, it is not necessary to limit R to this class of substituents. R may be any acyl radical derived from an organic acid by the removal of the hydroxyl group. It includes radicals derived from carboxylic acids, sulfonic acids and the like. Furthermore, R may also include loweralkyl esters.

In the most peferred embodiments of the present invention R and R each may be hydroxy or loweralkoX y, R is loweralkyl, R is CN and R is acetyl.

The present invention also provides a process for preparing the L form of a compound of the formula:

which comprises hydrolyzing the L form of a compound of the formula:

R2 R cm-b-u.

N NHa R1- wherein R, R R R and R are as previously defined.

The present invention also provides a process for preparing the L form of a compound of theformula:

which comprises aminating the L form of a compound of the formula:

l a R- GHz-Cf-Rs NH R1 hydroxylamine and O-(2,4-dinitrophenyl)hydroxylamine, hydroxylamine-O-su1fonic acid and its esters or any other suitable aminating agent. In general, the amination reaction is carried out in a solvent at a temperature ranging from 70 to +150 C. Suitable solvents include water, methanol, ethanol, ethyl acetate, diethyl ether, hexane, chloroform, methylene chloride and the like. In a preferred embodiment of this invention the reaction is carried out with chloramine or methoxyamine at a temperature of from 30 to +100 C. and more preferably from 15 to +70 C.

After forming the aminated intermediate products of the present invention, they may be hydrolyzed with aqueous acid or base under moderate conditions to remove the acyl group. When other substituent groups such as the 3,4-dimethoxy or 3,4-dibenzyloxy are present in the R group, these can simultaneously be converted to hydroxyl groups under somewhat more drastic conditions for hydrolysis. Similarly, the various R groups can be converted to the carboxyl group by varying the hydrolysis conditions. In general, the hydrolysis is carried out at a temperature of from about room temperature to 175 C., preferably 75 C. to 165 C. When it is desired to simultaneously convert the 3,4-dimethoxy or 3,4-dibenzyloxy to hydroxyl groups along with hydrolysis of the acyl radical, it is preferred that a concentrated (preferably fortified) hydrohalic acid such as hydrochloric or hydrobromic acid be used at a temperature of from 100 C. to 165 C. When such substituents are not present or it is not desired to convert the substituent groups, much less drastic conditions can be used and either an acid or a base in water will suifice for hydrolysis.

The following examples are presented to further illustrate the invention.

EXAMPLE 1 A. L-a-(l-acetylhydrazino) a methyl-p-(3,4-dirnethoxyphenyl)propionitrile.-Sodium hydride (250 mg., 55% in mineral oil, 5.2 mmoles) is washed with hexane and suspended in 6 ml. of DMSO. To this mixture is added a solution of L-a-acetamido-a-methyl-p-(3,4-dimethoxyphenyl)propionitrile (1.05 g., 4 mmoles) in 10 ml. of DMSO. After the gas evolution subsides minutes) the solution is cooled to 15 C. and a solution of chloramine (4.5 mmoles) in 12 ml. of dry ether is added over a period of two minutes. After 12 hours of agitation at room temperature, a few drops of acetic acid is added and the mixture is concentrated in vacuo. The resulting syrup is partitioned between water and chloroform. The organic layer is dried, the solvent removed and the residue is crystallized from ethyl acetate and ether to yield crystalline material.

An analytical sample is prepared by recrystallization from methanol, M.P. 121-123 C.

Analysis.-Calcd. for C H N O (percent): C, 60.63; H, 6.91; N, 15.15. Found (percent): C, 60.82; H, 7.10; N, 15.21.

B. Lot-hydrazino a methyl-18-(3,4-dihydroxyphenyl) propionic acid.-A solution of the product from the previous step (150 mg.) in 2.5 ml. of concentrated hydrochloric acid is heated in a sealed tube at 120 C. for 1 /2 hours. The resulting mixture is evaporated to dryness in vacuo and the product leached out with ethanol. The hydrazino acid is precipitated by addition of diethylamine to pH 6.4, the mixture filtered and the precipitate washed with ethanol and dried to yield L-a-hydrazino-a-methyl-B- (3,4 dihydroxyphenyl)propionic acid. Recrystallization from water containing a small amount of sodium bisulfite yields the product, M.P. 208 dec., [u] =17.3 (c.=2, CH OH).

EXAMPLE 2 A. L-a-(1-acetylhydrazino)-u-ethyl-;9-(3,4 dimethoxyphenyl)propionitrile-Sodium hydride (250 mg., 55% in mineral oil, 5.2 mmoles) is washed with hexane and suspended in 6 ml. of DMSO. To this mixture is added a solution of L-a-acetamido-a-ethyl-B-(3,4 dimethoxyphenyl) propionitrile (4 mmoles) in 10 ml. of DMSO. After the gas evolution subsides (15 minutes) the solution is cooled to 15 C. and a solution of chloramine (4.5 mmoles) in 12 ml. of dry ether is added over a period of two minutes. After 12 hours of agitation at room temperature a few drops of acetic acid is added and the mixture is concentrated in vacuo. The resulting syrup is partitioned between water and chloroform. The organic layer is dried, the solvent removed and the residue is crystallized from ethylacetate and ether to yield crystalline material.

B. L-a-ethyl a hydrazino-fi-(3,4-dihydroxyphenyl) propionic acid.--A solution of the product from the previous step in 2.5 ml. of concentrated hydrochloric acid is heated in the sealed tube at 120 C. for 1%. hours. Using the procedure of Example 1B, the hydrazino acid is obtained.

EXAMPLE 3 A. L-m-(l-acetylhydrazino) a methyl-fl-(3-hydroxy- 4-methoxypheny1)-propionitrile.-To a solution of Laacetamido-a-methyl-fi-(3-hydroxy 4 methoxyphenyl) propionitrile (4 mmoles) in 10 ml. of DMSO is added 8 mmoles of potassium t-butoxide. After 15 minutes the solution is cooled to 15 C. and a solution of chloramine (4.5 mmoles) in 12 ml. of dry ether is added over a period of two minutes. After 12 hours of agitation at room temperature a few drops of acetic acid is added and the mixture is concentrated in vacuo. The resulting syrup is partitioned between water and chloroform. The organic layer is dried, the solvent removed and the residue is crystallized from ethylacetate and ether to yield crystalline material.

B. L-ot-hydrazino a methyl-13-(3,4-dihydroxyphenyl)- propionic acid-A solution of the product from the previous step in 2.5 ml. of concentrated hydrochloric acid is heated in the sealed tube at 120 C. for 1 /2 hours. Utilizing the procedure of Example 1B, the hydrazino acid is obtained.

EXAMPLE 4 A. L-u-(l-acetylhydrazino) a methyl-B-(SA-dihydroxyphenyl) propionitrile.-Potassium hydride (13 mmoles, 55 in mineral oil) is washed with hexane and suspended in 6 ml. of DMSO. To this mixture is added a solution of L-u-acetamido-a-methyl-B-(3,4-dihydroxyphenyl)propionitrile (4 mmoles) in 10 ml. of DMSO. After the gas evolution subsides (15 minutes) the solution is cooled to 15 C. and a solution of O-2,4-dinitrophenylhydroxylamine (4.5 mmoles) in 12 ml. of dry dioxane is added over a period of two minutes. After 12 hours of agitation at room temperature a few drops of acetic acid is added and the mixture is concentrated in vacuo. The resulting syrup is partitioned between dilute NaOH solution and ether. The organic layer is dried, the solvent removed and the residue is crystallized from ethylacetate and ether to yield crystalline material.

B. L a hydrazino a methyl-fl-(3,4-dihydroxyphenyl)propionic acid.-A solution of the product from the previous step in 2.5 ml. of concentrated hydrochloric acid is heated to reflux for 1 /2 hours. Utilizing the procedure of Example 1B, the hydrazino acid is obtained.

EXAMPLE 5 A. L a hydrazino on methyl-fl-(3,4-dimethoxyphenyl)propionic acid.To an ice cold solution of L uamino a methyl B (3,4-dimethoxyphenyl)propionic acid hydrochloride (2.2 g., 8 mmoles) in 2.5 N sodium hydroxide is added 1.8 g. (16 mmoles) of hydroxylamine O-sulfonic acid. After 10 minutes, the mixture is heated at C. for one hour. The solution is acidified with hydrochloric acid and evaporated to dryness in vacuo. The residue is digested with ethanol and the crude product precipitated by addition of diethylamine to pH 6.5. The mixture is purified by chromatography. After recrystallization from water L a hydrazino-a-methyl-fl-(3,4-dimethoxy- -5 phenyl)propionic acid is obtained, M.P. 222-224 C. dec.

Analysis.--Calcd. for C H N O -H O: C, 52.93; H, 7.40; N, 10.29. Found: C, 53.01; H, 7.46; N, 10.28.

B. L a hydrazino a methyI-B-(BA-dihydroxyphenyl)propionic acid.A mixture of L a (3,4-dimethoxybenzyl) u hydrazino-propionic acid (10.0 g., 32.2 mmoles) and 150 ml. of concentrated hydrochloric acid is heated in a sealed tube at 120 C. for two hours. The resulting mixture is evaporated to dryness in vacuo and the product leached out with ethanol. The hydrazino acid is precipitated by addition of diethylamine to pH 6.4, the mixture filtered and the precipitate washed with ethanol and dried to yield L a hydrazino-a-methyl-B-(3,4-dihydroxyphenyl)propionic acid. Recrystallization from water containing a small amount of sodium bisulfite yields the product, M.P. 208 C. dec., [a] =17.3 C. (c.-=2, CH OH).

Analysis.-Calcd. for C H N -H O: C, 49.17; H, 6.60; N, 11.47. Found: C, 49.13; H, 6.74; N, 11.19.

EXAMPLE 6 A. L u (1 benzoylhydrazino)-a-methyl-fl-(3,4-dibenzyloxyphenyl)propionamide.-Sodium hydride (250 mg., 55% in mineral oil ,5.2 mmoles) is washed with hexane and suspended in 6 ml. of DMSO. To this mixture is added a solution of L a benzamido-a-methyl-fl-(3,4- dibenzyloxyphenyl)propionamide (4 mmoles) in 10 ml. of DMSO. After the gas evolution subsides (15 minutes) the solution is cooled at 15 C. and a solution of chloramine (4.5 mmoles) in 12 ml. of dry ether is added over a period of two minutes. After 12 hours of agitation at room temperature a few drops of acetic acid is added and the mixture is concentrated in vacuo. The resulting syrup is partitioned between water and chloroform. The organic layer is dried, the solvent removed and the residue is crystallized from ethylacetate and ether to yield crystalline material.

B. L oz hydrazino oz methyl-p-(3,4-dihydroxyphenyl)propionic acid.A solution of the product from the previous step in 2.5 ml. of concentrated hydrochloric acid is heated in the sealed tube at 100 C. for 1% hours. Utilizing the procedure of Example 1B, the hydrazino acid is obtained.

EXAMPLE 7 A. L a acethydrazino-a-ethyl-B-(3,4-dibenzyloxyphenyl)propionitrile. Sodium hydride (250 mg., 55% in mineral oil, 5.2 mmoles) is washed with hexane and suspended in 6 m1. of DMSO. To a solution of L-a-acetamido u ethyl B (3,4-dibenzyloxyphenyl)propionitrile (4 mmoles) in 10 ml. of DMSO is added mmoles of sodium methoxide. After 15 minutes the solution is cooled to 15 C. and a solution of chloramine (4.5 mmoles) in 12 ml. of dry ether is added over a period of two minutes. After 12 hours of agitation at room temperature a few drops of acetic acid is added and the mixture is concentrated in vacuo. The resulting syrup is partitioned between water and chloroform. The organic layer is dried, the solvent removed and the residue is crystallized from ethylacetate and ether to yield crystalline material.

B. L a hydrazino-a-ethyl-B-(3,4-dihydroxyphenyl) propionic acid.A solution of the product from the previous step in 2.5 ml. of concentrated hydrochloric acid is heated in the sealed tube at 120 C. for 1% hours. Utilizing the procedure of Example 1B, the hydrazino acid is obtained.

EXAMPLE 8 A. L oz (l acetylhydrazino) a-methyl-B-(3,4-dimethoxyphenyl)propionitrile.Sodium hydride 250 mg., 55% in mineral oil, 5.2 mmoles) is washed with hexane and suspended in 6 ml. of DMSO. To this mixture is added a solution of L a acetamido-a-methyl-fl-(3,4-dimethoxyphenyl)propionitrile (4 mmoles) in 10 ml. of DMSO. After the gas evolution subsides minutes) the solution is cooled to 15 C. and a solution of methoxyamine (4.5 mmoles) in 12 m1. of dry ether is added over a period of two minutes. After 12 hours of agitation at room temperature a few drops of acetic acid is added and the mixture is concentrated in vacuo. The resulting syrup is partitioned between water and chloroform. The organic layer is dried, the solvent removed and the residue is crystallized from ethyl acetate and ether to yield crystalline material.

B. L oz hydrazino a methyl-fi-(SA-dihydroxyphenyl)propionic acid.L-a-acethydrazino a methyl-13- (3,4-dimethoxyphenyl)propionitrile (0.01 mole) is heated to 120 for 1% hours in a sealed tube with concentrated hydrochloric acid for 3 hours. Concentration to dryness in vacuo yields L u-hydrazino-a-methyl-fl-(3,4-dihydroxyphenyl)propionic acid hydrochloride salt.

The hydrazino acid is freed from its salt by the use of an ion exchange resin or by dissolving in a minimum amount of ethyl alcohol and with an equimolar amount of ethyleneoxide. The precipitated hydrazino acid is recrystallized from water containing 0.1% sodium bisulphite.

EXAMPLE 9 A. L-a-(l acetylhydrazino)a-ethyl-fl-(B hydroxy-4- methoxyphenyl) N,N dimethylpropionamide.-To a solution of L-a-acetamido a ethyl-fi-(3-hydroxy-4-methoxyphenyl) N,N dimethylpropionamide (0.1 mole) in diozane ml.) is added potassium t-butoxide (0.12 moles). After stirring the mixture at room temperature for 1 hour, O-phenylhydroxylamine (0.12 mole) is added. The mixture is heated at 50 C. for 1 hour and poured in water, extracted with chloroform, dried, and evaporated to yield L-a-(l-acetylhydrazino)-a-ethyl-,8-(3-hydroxy-4-methoxyphenyl -N,N-dimethylpropionamide.

B. L-a-ethyl a hydrazino-,8-(3,4-dihydroxyphenyl) propionic acid.-A solution of the product from the previous step in 2.5 ml. of concentrated hydrochloric acid is heated in the sealed tube at C. for 1% hours. Utilizing the procedure of Example 1B, the hydrazino acid is obtained.

What is claimed is:

1. A process for preparing the L form of a compound of the formula:

R: R- GHQ-(i7 C O O H NH-NHz R1- wherein:

R and R each may be loweralkoxy, phenyloxy, benzyloxy or hydroxy; R is hydrogen or loweralkyl; R is CN, COOH, CONH or /Rs 0 0 N wherein R is loweralkyl; and R is loweralkanoyl; which comprises:

(a) aminating with chloramine or methoxyamine at a wherein R, R R R and R are as previously defined to obtain the L form of a compound of the formula:

7 8 wherein R, R R R and R are as previously de- FOREIGN PATENTS fined; and 370798 9/1963 Switzerland 260583 B (b) hydrolyzing with a concentrated hydrohalic acid 940,596 10/1963 Great Britain 260 519 at a temperature of from about room temperature to OTHER REFERENCES 175 C. the L form of a compound of the formula: 5

Smith: Open-Chain Nitrogen Compounds, vol. 11, W.

A. Benjamin, Inc., New York, N.Y., 1966, pp. 144-146.

Karady et al., Journal of Organic Chemistry, vol. 36, R CH2$R3 No. 14, pp. 1949-51 (1971).

NNH; 10 Journal fiir Praktische Chemie., vol. 36, pp. 29-41 Rt 1 (1967).

Chemical Abstracts, vol. 51, p. 1761b 1951 J.A.C.S., vol. 77, p. 3131 1955 Where R3 and R4 are as defined 15 LORRAINE A. WEINBERGER, Primary Examiner References Cited P. J. HAGAN, Assistant Examiner UNITED STJIXTES PATENTS s. cl X 3,366,679 1/1968 Remhold et a1. 260519 3,493,602 2/1970 Suranyi et a1. 260519 20 26046513, 559E 

